Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade Journal Article
| Authors: | Zhang, Q.; Luo, J.; Wu, S.; Si, H.; Gao, C.; Xu, W.; Abdullah, S. E.; Higgs, B. W.; Dennis, P. A.; van der Heijden, M. S.; Segal, N. H.; Chaft, J. E.; Hembrough, T.; Barrett, J. C.; Hellmann, M. D. |
| Article Title: | Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade |
| Abstract: | The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n = 978) and on-treatment (n = 171) ctDNA samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab (+/- the anti-CTLA4 therapy tremelimumab). Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival (OS) and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer progression-free survival and OS and increased objective response rate, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of "molecular response" using ctDNA, incorporating both pretreatment and on-treatment VAF, that predicted long-term survival similarly to initial radiologic response while also permitting early differentiation of responders among patients with initially radiologically stable disease. SIGNIFICANCE: In a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A "molecular response" metric identified long-term responders and adjudicated benefit among patients with initially radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints. |
| Keywords: | chemotherapy; ipilimumab; solid tumors; lung-cancer; pd-l1; nivolumab; pembrolizumab; ctdna |
| Journal Title: | Cancer Discovery |
| Volume: | 10 |
| Issue: | 12 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-12-01 |
| Start Page: | 1842 |
| End Page: | 1853 |
| Language: | English |
| ACCESSION: | WOS:000595600800022 |
| DOI: | 10.1158/2159-8290.Cd-20-0047 |
| PROVIDER: | wos |
| PUBMED: | 32816849 |
| PMCID: | PMC8358981 |
| Notes: | Article -- Source: Wos |
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